Diagnostics for childhood tuberculosis: a marathon rather than a sprint
Authors: Toyin Omotayo Togun, Beate Kampmann
Journal: The Lancet Infectious Diseases (2023)

Each year, an estimated 1·2 million incident cases of tuberculosis occur in children younger than 15 years globally, and approximately a quarter of these children will die from tuberculosis.1WHOGlobal tuberculosis report 2022.https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022Date: 2022Date accessed: October 3, 2023Google Scholar The majority of the childhood tuberculosis cases and deaths occur in low-income and middle-income countries, where difficulties and delays, primarily in tuberculosis case detection, contribute to poor outcomes in children.2Storla DG Yimer S Bjune GA A systematic review of delay in the diagnosis and treatment of tuberculosis.BMC Public Health. 2008; 8: 15Crossref PubMed Scopus (719) Google Scholar, 3Dodd PJ Yuen CM Sismanidis C Seddon JA Jenkins HE The global burden of tuberculosis mortality in children: a mathematical modelling study.Lancet Glob Health. 2017; 5: e898-e906Summary Full Text Full Text PDF PubMed Scopus (262) Google Scholar The paucibacillary nature of tuberculosis in children constitutes a major obstacle to accurately estimating the burden of disease and achieving quality management.4Nelson LJ Wells CD Tuberculosis in children: considerations for children from developing countries.Semin Pediatr Infect Dis. 2004; 15: 150-154Crossref PubMed Scopus (36) Google Scholar Therefore, diagnosis of childhood tuberculosis is most often presumptive, based on epidemiological and clinical parameters that lack specificity.5Roy RB Whittaker E Seddon JA Kampmann B Tuberculosis susceptibility and protection in children.Lancet Infect Dis. 2019; 19: e96-108Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar As a result, WHO has prioritised the need for a rapid, preferably non-sputum-based diagnostic solution for childhood tuberculosis.1WHOGlobal tuberculosis report 2022.https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022Date: 2022Date accessed: October 3, 2023Google Scholar Such a test should enable fast and accurate distinction between tuberculosis disease and other respiratory infections, irrespective of HIV and nutritional status, and should be applicable for use at lower levels of the health-care system in resource-limited settings.6Nicol MP Gnanashanmugam D Browning R et al.A blueprint to address research gaps in the development of biomarkers for pediatric tuberculosis.Clin Infect Dis. 2015; 61: S164-S172Crossref Scopus (26) Google Scholar In The Lancet Infectious Diseases, Laura Olbrich and colleagues report findings from a prospective diagnostic evaluation of the non-sputum-based Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR; Cepheid, Sunnyvale, CA, USA) in a multinational cohort of 639 children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis (or both).7Olbrich L Verghese VP Franckling-Smith Z et al.Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries.Lancet Infect Dis. 2023; (published online Oct 30.)https://doi.org/10.1016/S1473-3099(23)00491-7Summary Full Text Full Text PDF Scopus (1) Google Scholar The Cepheid MTB-HR is a candidate test that measures a three-gene mRNA transcriptomic signature from fingerstick blood in a prototype cartridge, utilising the Cepheid GeneXpert platform, to derive an MTB-HR TB-score based on cycle threshold values. The test previously showed promising diagnostic accuracy in a small, adult cohort study, with an area under the receiver operating characteristic curve (AUC) of 0·88 (95% CI 0·83–0·94), 80% sensitivity (95% CI 76–85), and 94% specificity (95% CI 91–96) compared with a composite microbiological reference standard of Xpert MTB/RIF Ultra and culture.8Sutherland JS van der Spuy G Gindeh A et al.Diagnostic accuracy of the Cepheid 3-gene host response fingerstick blood test in a prospective, multi-site study: interim results.Clin Infect Dis. 2022; 74: 2136-2141Crossref PubMed Scopus (38) Google Scholar Using the same technology platform and TB-score cutoff thresholds as in the adult study,8Sutherland JS van der Spuy G Gindeh A et al.Diagnostic accuracy of the Cepheid 3-gene host response fingerstick blood test in a prospective, multi-site study: interim results.Clin Infect Dis. 2022; 74: 2136-2141Crossref PubMed Scopus (38) Google Scholar the Article by Olbrich and colleagues is the first assessment of the performance of MTB-HR in children. In their study, MTB-HR TB-score distinguished children with culture-confirmed tuberculosis from those with unlikely tuberculosis with an AUC of 0·85 (95% CI 0·80–0·89) and demonstrated sensitivity and specificity of 59·8% (95% CI 50·8–68·4) and 90·3% (95% CI 85·5–94·0), respectively. It is encouraging that the reported diagnostic accuracy of the MTB-HR against culture-confirmed tuberculosis was consistent, irrespective of the age group and nutritional status of the children. However, the diagnostic performance overall and in sub-groups decreased considerably when using a composite clinical reference standard of all children diagnosed with tuberculosis, irrespective of microbiological confirmation. In this scenario, which is more reflective of routine clinical practice, the sensitivity of the test dropped to 29·6% (25·4–34·2). The diagnostic performance of the MTB-HR TB score in children younger than 15 years suggests that it might not be useful as a standalone test for confirming diagnosis of childhood tuberculosis because of its suboptimal sensitivity relative to the WHO-endorsed target product profile for a new diagnostic test for tuberculosis in children (≥66% for intrathoracic tuberculosis).9Denkinger CM Kik SV Cirillo DM et al.Defining the needs for next generation assays for tuberculosis.J Infect Dis. 2015; 211: S29-S38Crossref PubMed Scopus (120) Google Scholar Additionally, given that the MTB-HR tuberculosis score was positive in only about a third of all children diagnosed with and treated for tuberculosis, we can conclude that its performance is not superior to the currently available tuberculosis diagnostic tests. However, the MTB-HR could potentially add value to the diagnostic algorithms for tuberculosis in children when used in conjunction with conventional pathogen detection tests. This assertion is supported by the fact that combining the baseline MTB-HR result with one Xpert MTB/RIF Ultra on a respiratory sample identified 71·2% of children with microbiologically confirmed tuberculosis. However, given that microbiological confirmation of tuberculosis disease is achieved in only a proportion of all children who commence tuberculosis treatment, an urgent need remains for further development of improved methods with increased sensitivity. Nevertheless, we agree with the authors that the performance of the MTB-HR TB-score could possibly be further optimised by identifying a child-specific MTB-HR diagnostic cutoff, rather than using adult parameters. This idea is supported by published data that show essential differences in immune parameters between adults and children with tuberculosis, which also translate into different gene expression profiles.10Anderson ST Kaforou M Brent AJ et al.Diagnosis of childhood tuberculosis and host RNA expression in Africa.N Engl J Med. 2014; 370: 1712-1723Crossref PubMed Scopus (274) Google Scholar We must develop diagnostic tools that can perform accurately in a variety of epidemiological settings. In many tuberculosis-endemic countries, HIV is an additional high prevalence condition, often co-occurring in children. Although the reported diagnostic accuracy of the MTB-HR was lower in children living with HIV in this study, the size of the HIV cohort was too small to draw definitive conclusions on the performance of the test in this group. Furthermore, because the MTB-HR is based on the GeneXpert platform, costs and place of delivery of the test are also important to consider when planning implementation strategies, especially in resource-constrained, tuberculosis-endemic countries. In summary, these findings represent progress in childhood tuberculosis diagnosis, but we are still not where we need to be. We delcare no competing interests. Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countriesMTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. Full-Text PDF Open Access